Institute for Ageing and Health, Wolfson Research Centre, Newcastle University, Newcastle upon Tyne, UK.
J Neural Transm (Vienna). 2011 May;118(5):737-45. doi: 10.1007/s00702-011-0626-5. Epub 2011 Mar 26.
Neuropathological features in Alzheimer's Disease (AD) include the presence of hyperphosphorylated forms of the microtubule-associated tau protein (tau) in hippocampal neurones. Numerous studies indicate a neuroprotective effect of calcium-binding proteins (Ca2+ binding proteins) in neurodegenerative diseases (e.g., AD). Secretagogin is a newly described Ca2+ binding protein that is produced by pyramidal neurones of the human hippocampus. Recently, secretagogin expressing hippocampal neurones were demonstrated to resist tau-induced pathology in AD in contrast to the majority of neighbouring neurones. This suggested a neuroprotective effect of secretagogin in hippocampal neurones. Here, we investigated secretagogin expression in wild type (wt) mice as well as in hemizygous and homozygous P301L tau transgenic (tg) mice, which show pronounced and widespread tau pathology in hippocampal neurones. Secretagogin expression was analyzed at the immunohistochemical and biochemical levels in brains of age-matched wt and hemi- and homozygous tau tg mice. In wt mice hippocampal secretagogin-immunoreactive neurones were invariably detected, while immunoreactivity was much lower (P < 0.001) in tau tg mice. Of note, hippocampal secretagogin immunoreactivity was absent in 62.5% of homozygous tau tg mice. In line with this finding, Western blot analysis demonstrated a significant reduction in protein expression levels of secretagogin in homozygous tau tg compared to wt mice. Our results suggest that increased levels of tau negatively influence secretagogin expression in the hippocampus of tau tg mice.
阿尔茨海默病（AD）的神经病理学特征包括海马神经元中微管相关tau 蛋白（tau）的过度磷酸化形式的存在。大量研究表明钙结合蛋白（Ca2+结合蛋白）在神经退行性疾病（如 AD）中具有神经保护作用。分泌素是一种新描述的 Ca2+结合蛋白，由人类海马体的锥体细胞产生。最近，研究表明表达分泌素的海马神经元能够抵抗 AD 中 tau 诱导的病理学，而大多数邻近神经元则不能。这表明分泌素对海马神经元具有神经保护作用。在这里，我们研究了野生型（wt）小鼠以及半合子和纯合 P301L tau 转基因（tg）小鼠中分泌素的表达，这些小鼠在海马神经元中表现出明显且广泛的 tau 病理学。在年龄匹配的 wt 和半合子和纯合 tau tg 小鼠的大脑中，通过免疫组织化学和生化水平分析了分泌素的表达。在 wt 小鼠中，海马分泌素免疫反应性神经元始终被检测到，而在 tau tg 小鼠中，免疫反应性明显降低（P <0.001）。值得注意的是，在 62.5%的纯合子 tau tg 小鼠中，海马分泌素免疫反应性缺失。与这一发现一致，Western blot 分析表明，与 wt 小鼠相比，纯合子 tau tg 中分泌素的蛋白表达水平显著降低。我们的结果表明，tau 水平的升高会负性影响 tau tg 小鼠海马体中分泌素的表达。
